Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis

N Engl J Med. 2025 May 15;392(19):1883-1892. doi: 10.1056/NEJMoa2415988. Epub 2025 Apr 8.

Abstract

Background: Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for multiple sclerosis have limited effects on disability accrual unrelated to relapses, which is thought to be partially caused by chronic, nonresolving neuroinflammation within the central nervous system. Tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system. There are no approved treatments for nonrelapsing secondary progressive multiple sclerosis.

Methods: In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with nonrelapsing secondary progressive multiple sclerosis, in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed disability progression that was sustained for at least 6 months, assessed in a time-to-event analysis.

Results: A total of 1131 participants underwent randomization: 754 were assigned to receive tolebrutinib and 377 to receive placebo. The median follow-up was 133 weeks. A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.88; P = 0.003). Serious adverse events occurred in 15.0% of the participants in the tolebrutinib group and in 10.4% of those in the placebo group. A total of 4.0% of the participants in the tolebrutinib group and 1.6% of those in the placebo group had increases in alanine aminotransferase levels to more than 3 times the upper limit of the normal range.

Conclusions: In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo. (Funded by Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.).

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase III
  • Multicenter Study

MeSH terms

  • Adult
  • Agammaglobulinaemia Tyrosine Kinase* / antagonists & inhibitors
  • Alanine Transaminase / blood
  • Disability Evaluation
  • Disease Progression
  • Double-Blind Method
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Middle Aged
  • Multiple Sclerosis, Chronic Progressive* / blood
  • Multiple Sclerosis, Chronic Progressive* / diagnosis
  • Multiple Sclerosis, Chronic Progressive* / drug therapy
  • Protein Kinase Inhibitors* / adverse effects
  • Protein Kinase Inhibitors* / therapeutic use
  • Treatment Outcome
  • Tyrosine Kinase Inhibitors* / administration & dosage
  • Tyrosine Kinase Inhibitors* / adverse effects

Substances

  • Agammaglobulinaemia Tyrosine Kinase
  • Protein Kinase Inhibitors
  • Tyrosine Kinase Inhibitors
  • Alanine Transaminase

Associated data

  • ClinicalTrials.gov/NCT04411641